Mesenchymal stem cells inhibited the differentiation of MDSCs via COX2/PGE2 in experimental sialadenitis

Abstract

Background: Mesenchymal stem cells (MSCs) can regulate innate and adaptive immune systems through interacting with immune cells directly and secreting multiple soluble factors. Due to their immunosuppressive properties, MSC transplantation has been applied to treat many clinical and experimental autoimmune diseases. However, the therapeutic effects and mechanisms by which MSCs regulate myeloid cells in Sjögren's syndrome (SS) still remain elusive. Methods: The number and immune-suppressive activity of myeloid-derived suppressor cells (MDSCs), polymorphonuclear MDSCs (PMN-MDSCs), and monocytic MDSCs (M-MDSCs) were determined in non-obese diabetic (NOD) mice with sialadenitis and in NOD mice with human umbilical cord-derived MSC (UC-MSC) transplantation. Bone marrow cells were cultured with MSC-conditioned medium (MSC-CM) for 4 days. The number and immune-suppressive gene of MDSCs were detected by flow cytometry or qRT-PCR. Results: The results showed that the number of MDSCs and PMN-MDSCs was higher and M-MDSCs were lower in NOD mice with sialadenitis. UC-MSCs ameliorated SS-like syndrome by reducing MDSCs, PMN-MDSCs, and M-MDSCs and promoting the suppressive ability of MDSCs significantly in NOD mice. UC-MSCs inhibited the differentiation of MDSCs. In addition, UC-MSCs enhanced the suppressive ability of MDSCs in vitro. Mechanistically, MSCs inhibited the differentiation of MDSCs and PMN-MDSCs via secreting prostaglandin E2 (PGE2) and inhibited the differentiation of M-MDSCs through secreting interferon-β (IFN-β). Conclusions: Our findings suggested that MSCs alleviated SS-like symptoms by suppressing the aberrant accumulation and improving the suppressive function of MDSCs in NOD mice with sialadenitis.

Myeloid-Derived Suppressor Cells Dampen Airway Inflammation Through Prostaglandin E2 Receptor 4

“…Similarly, we found that PGE2 enhanced GM-CSF/IL-6-induced PMN- and M-MDSC activity through the EP4 receptor from cultured bone marrow cells. In line with these and related previous findings ( 23 , 25 – 27 ), we found that PGE2 upregulated Arg1 and Nos2 expression in murine bone marrow cells through the EP2 and EP4 receptors. As previously discussed, arginase-1 is one of the main products of MDSCs that contribute to their anti-inflammatory effector functions.…”

“…PGE2 has previously been used to enhance the generation of MDSCs from human PBMCs ( 21 ) and from murine bone marrow cells ( 22 , 23 ) in vitro . Shi et al.…”

Treatment of Sjögren’s Syndrome with Mesenchymal Stem Cells: A Systematic Review

“…The method of MSC transplantation in mice and humans appeared to be broadly consistent across the studies. Intravenous injections of MSCs were used in all studies [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ], with the exception of one [ 30 ] in which MSCs were administered intraperitoneally. A variety of cocultures were used such as UCMSCs cocultured with peripheral blood mononuclear cells (PBMCs) [ 31 , 32 ], and MSCs cocultured with monocyte-derived dendritic cells [ 26 ] or CD4 + T cells and MSC coculture experiments [ 33 ].…”

Umbilical cord mesenchymal stem cells enhance the therapeutic effect of imipenem by regulating myeloid-derived suppressor cells in septic mice

“…The MDSCs phenotype differs between mice and humans. Mouse MDSCs are characterized as CD11b + Gr-1 + cells and can be further divided into CD11b + Ly6G low Ly6C high monocytic MDSCs (M-MDSCs) and CD11b + Ly6G high Ly6C low granulocytic MDSCs (G-MDSCs) (14). Human MDSCs are CD11b + CD33 + HLA-DRcells (15).…”